The Obesity-Associated FTO Gene Encodes a 2-Oxoglutarate-Dependent Nucleic Acid Demethylase

Chemistry Research Laboratory and Oxford Centre for Integrative Systems Biology, University of Oxford, 12 Mansfield Road, Oxford, Oxon OX1 3TA, UK.
Science (Impact Factor: 33.61). 12/2007; 318(5855):1469-72. DOI: 10.1126/science.1151710
Source: PubMed


Variants in the FTO (fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics
analysis that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate–dependent oxygenases. We find that recombinant murine
Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production
of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes
to the nucleus in transfected cells. Studies of wild-type mice indicate that Fto messenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and that
Fto mRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the
physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass.

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    • "Within this context, studies have sought evidence regarding the relationship between FTO polymorphism and the risk of obesity (Frayling et al., 2007; Karasawa et al., 2010). Although the role of the FTO gene product remains unclear, some knowledge does exist: FTO is expressed in human and animal tissues, with the highest expression in the brain, mainly in the hypothalamus (Gerken et al., 2007), an area that regulates energy homeostasis (Caruso et al., 2013). "
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    ABSTRACT: Objectives The aim of the present study was to evaluate the relationship between the rs9939609 fat mass and obesity-associated (FTO) polymorphism and cardiorespiratory fitness (CRF) with overweight/obesity outcomes in youth.Methods This study included 420 youths, comprising 211 boys and 209 girls aged 7–17. Overweight/obesity were evaluated by body mass index (BMI), waist circumference (WC), and the percentage of fat (PF) according to two skinfold thickness measurements. Genotyping of the rs9939609 polymorphism was conducted using real-time Polymerase Chain Reaction (PCR) utilizing TaqMan® probes, and CRF was evaluated through a 9-minute run/walk test, categorized as fit or unfit. Logistic regression was utilized to evaluate a possible association between the polymorphism and CRF, with three obesity indicators evaluated.ResultsIndividuals with the genotype risk (AA) of FTO polymorphism rs9939609 showed higher prevalence of overweight/obesity, as evaluated by BMI (OR: 3.21; CI: 1.71–6.05), WC (OR: 2.59; CI: 1.35–4.97), and PF (OR: 2.59; CI: 1.36–4.92). Additionally, students with the AA genotype in the unfit model had a significant odds ratio for obesity (OR: 4.40; CI: 1.83–10.61 for BMI; OR: 3.54; CI: 1.58–7.96 for WC), whereas we did not observe associations between the AA genotype with BMI and WC using the fit model. Conversely, PF was associated with the AA genotype only in the fit model (OR: 3.24; CI: 1.26–8.34).Conclusions This study demonstrated that the rs9939609 (FTO) polymorphism showed a relationship with obesity in the population studied and an interaction with CRF. Students with low levels of CRF and the AA genotype have a higher risk of being overweight/obese. This association was not found in students with higher levels of CRF. Am. J. Hum. Biol., 2015. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Oct 2015 · American Journal of Human Biology
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    • "The FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase (Gerken et al., 2007) but is also a transcriptional coactivator (Wu et al., 2010) and a possible regulator of telomere length (Dlouha et al., 2012). FTO is abundantly expressed in the hypothalamus, and epidemiological and functional studies have suggested it is directly involved in the regulation of energy intake (Cecil et al., 2008; Haupt et al., 2009). "
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    ABSTRACT: To investigate in a population sample of Portuguese young adults the association of the FTO variant rs9939609 with obesity, BMI, and body-fat and interaction with physical activity (PA) on obesity-susceptibility. SNP rs9939609 A/T was genotyped in 550 subjects (231 males and 319 females; 18-36 years old; mean age 21 years old) by TaqMan assay. PA was assessed with a validated self-reported questionnaire of IPAQ. We replicated the association of rs9939609-A risk allele with BMI (P = 0.04) and fat-mass (P = 0.031), and with overweight (including obesity) under a recessive model (P = 0.034). Stratified analyses showed (i) a significant association with overweight/obesity in inactive individuals (P = 0.02) but not in a group reporting participation in sports (P = 0.97). Spearman's correlation test suggested that the impact of a successive increase in PA was a decrease in the body-fat percentage (r = -0.16; P = 0.0002), which is accentuated for homozygous AA (r = -0.34; P = 0.002), and an increase in BMI (r = 0.14; P = 0.001), with a statistically significant correlation for homozygous TT (r = 0.22; P = 0.002). This study reveals interactions between rs9939609 and PA on obesity indices in Portuguese young adults, suggesting a change in the different body components (lean and fat mass) depending on the FTO genotypes. Am. J. Hum. Biol., 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Mar 2015 · American Journal of Human Biology
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    • "Important differences were apparent between studies. For example, the molecular pathways involving the Fto gene may greatly differ when considering (i) the response to long-term fasting in mice (Gerken et al. 2007) or (ii) total daily energy intake in sheep (Sebert et al. 2010). "

    Full-text · Dataset · Mar 2015
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